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BWT Pharma & Biotech

Pharmaceutical Water Requirements

PHARMA & BIOTECH

2 Pharmaceutical Water Requirements

Pharmaceutical WatersPotable waterPotable water/water intended for human consumptionPotable water, or water intended for human consumption, is also used as feed water for the production of purified water and water for injections. Potable water may be used to rinse product-contacting surfaces of equipment.

Potable water (treated)Treated potable water has the same uses as potable water and water intended for human consumption but has been treated to reduce its microbial content.

Purified Water (PW)Purified Water in bulkIs used as an excipient in the preparation of non-sterile products and as a starting material in the preparation of water for injection and pharmaceutical-grade pure steam. It is also used for rinsing purposes (cleaning of containers) and in the preparation of cleaning solutions.

Purified Water in containersIs Purified Water in bulk that has been filled and stored in conditions designed to assure the required microbiological quality. It must be free from any added substances.

Highly Purified Water (HPW)Is used in the preparation of medicinal products where bacterial endotoxins need to be controlled, except where water for injection is required. Current methods for the preparation include double-pass reverse osmosis, reverse osmosis combined with ultrafiltration and distillation.

Water for Injection (WFI)Sterilized Water for injectionIs used for dissolving or diluting substances or preparations for par-enteral administration.

Water for injection in bulkIs used in the manufacture of parenteral and ophtalmic products. It is also used for final rinsing of containers (e.g. primary packaging materials) and manufacture of these products.

Pure Steam (PS)Pure steam is evaporated above 100°C and used for humidification and sterilisation of e.g. porous goods. The level of steam satura-tion or dryness, and the amount of non-condensable gases are to be determined by the Pure Steam application. The condensate must comply with the respective WFI requirements.

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USP*/Ph. Eur.**

Purified Water

Parameter Unit USP Ph. Eur. (Bulk)TOC ppm C 0.50 0.5

Conductivity µS/cm@20°C – < 4.3

Conductivity µS/cm@25°C < 1.3 –

Nitrate (NO3) ppm – < 0.2

Heavy metals ppm as Pb – < 0.1

Aerobic bacteria CFU/ml < 100 < 100

Highly Purified Water

Parameter Unit USP Ph. Eur. (Bulk)TOC ppm C n.c.st. 0.5

Conductivity µS/cm@20°C n.c.st. < 1.1

Nitrate NO3 ppm n.c.st. < 0.2

Aerobic bacteria CFU/100ml n.c.st. < 10

Bacterial endotoxins l.U./ml n.c.st. < 0.25

Water for Injection

Parameter Unit USP Ph. Eur. (Bulk)TOC ppm C 0.50 0.5

Conductivity µS/cm@20°C – < 1.1

Conductivity µS/cm@25°C < 1.3 –

Nitrate (NO3) ppm – < 0.2

Aerobic bacteria CFU/100ml < 10 < 10

Bacterial endotoxins EU/ml < 0.25 –

Bacterial endotoxins l.U./ml – < 0.25

Pure Steam (condensate)

Parameter Unit USP Ph. Eur. (Bulk)TOC ppm C 0.50 n.c.st.

Conductivity µS/cm@25°C < 1.3 n.c.st.

Aerobic bacteria CFU/100ml < 10 n.c.st.

Bacterial endotoxins EU/ml < 0.25 n.c.st.

n.c.st. = no comparable standard

* current United States Pharmacopoeia, ** current European Pharmacopoeia

4 Pharmaceutical Water Requirements

Conductivity According to USPThree-stage Philosophy

1. In-line Measurement:A conductivity measurement without temperature compensation corres ponding to a measured temperature. If the conductivity is be-low 1.3 μS/cm at 25°C (or values according to Table A) the meas-urement is completed. If not, stage 2 is required.

Advantages of the in-line Measurement in Stage 1   Real-time information for conductivity and temperature

  Immediate limit value alarm

  Data output for recording and documentation of the water quality

  Calibrated measurement

  Avoiding of errors due to sampling, handling & transport

2. Laboratory Measurement:If the CO2 concentration of the sample is at equilibrium with the air and the conductivity is below 2.1 μS / cm at 25°C the measurement is completed. If not, stage 3 is required.

3. Laboratory Measurement:Add saturated KCI to the sample from stage 2 and measure pH and conductivity. The measured conductivity must be below the conduc-tivity value shown in Table 1 at the measured pH. If this is the case, the measurement is completed. If not, the water does not conform to the standard.

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Stage 1

Temp. °C µS/cm

0 0.6

5 0.8

10 0.9

15 1.0

20 1.1

25 1.3

30 1.4

35 1.5

40 1.7

45 1.8

50 1.9

55 2.1

60 2.2

65 2.4

70 2.5

75 2.7

80 2.7

85 2.7

90 2.7

95 2.9

100 3.1

Stage 3

pH µS/cm

5.0 4.7

5.1 4.1

5.2 3.6

5.3 3.3

5.4 3.0

5.5 2.8

5.6 2.6

5.7 2.5

5.8 2.4

5.9 2.4

6.0 2.4

6.1 2.4

6.2 2.5

6.3 2.4

6.4 2.3

6.5 2.2

6.6 2.1

6.7 2.6

6.8 3.1

6.9 3.8

7.0 4.6

Table AStage 1: Conductivity limits as a function of the temperatureStage 3: Conductivity limits as a function of the pH value

Systems, Solutions, Services6

Systems and Turnkey Solutions?We‘ve got what you‘re looking for!

With BWT systems and turnkey solutions you benefi t from the in-dustry leading product lines combining best process engineering, premium components and technologies, highest quality manufactur-ing and assembly, cGMP compliant documentation and validation, validated automation solutions and comprehensive services for the entire life-cycle.

Pre-treatmentDrinking water is mandatory as the basis for the production of pharmaceutical water, but such water is not available everywhere in the necessary quality and quantity. The use of BWT ULTRASTIL systems is a reliable method for the production of drinking water from raw water and as an optimal pre-treatment stage to protect downstream PW/HPW processes.

ULTRASTIL Raw-Water Ultrafi ltration   High recovery robust dead end ultrafi ltration   Optimal reduction of colloidal impurities (SDI15)

  Best retention rate for particles, germs, bacteria and viruses

  Continuous operation of downstream process equipment

  Signifi cant lifetime extension of downstream disposable fi lters and membranes

  Compact space saving skid design

ULTRASTIL

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PW/HPW GenerationPurifi ed Water or Highly Purifi ed Water is one of the most critical raw materials for pharmaceutical production and related industries. As such the qualities at the point of use are regulated in the different international pharmacopeia´s such as USP, EP, JP etc.

To safely achieve the defi ned qualities and maintain appropriate safety, alarm and action levels, it is important to deliver highest qualities to the storage & distribution systems. BWT pre-validated and tested PW/HPW generation products allow an optimal choice and technology for any kind of PW/HPW generation need, project requirement and budget. All systems are optional available with the unique SEPTRON® BIOSAFE the only integrated EDI/UF technology guaranteeing premium microbiological quality and safety.

SEPTRONLINE – standard compact PW/HPW systems   Integrated RO, SEPTRON® EDI

  Small footprint

  Semi-automatic chemical sanitization

  Attractive pricing

  Easy modular upgrade option within the series

  Separate pre-treatment, ELITE RS hygienic softening with SANISAL salt

  0.15 - 0.3 m³/h and 0.4 - 2.4 m³/h series

OSMOLINE – standard compact PW/HPW systems   Open skid RO, SEPTRON® EDI   Small footprint

  Automatic hot water sanitization >80°C

  Multijoint bloc velve technology

  Easy modular upgrade option

  Attractive pricing

  0.4 - 2.4 m³/h series

SEPTRONLINE OSMOLINE

Systems, Solutions, Services8

OsmoVision – innovative integrated high effi ciency PW/HPW system   Open skid pre-treatment, softening, RO, SEPTRON® EDI   Maximum recovery for lowest operating cost

  Free chlorine & CO2 tolerance by patented process design

  Continuous chemical sanitization without added substances

  MULTIJOINT diaphragm bloc valve technology

  0,5 - 10m³/h single skid or >10m³/h multi skid solutions

OSMOTRON® – the world best-selling PW/HPW system   Open skid pre-treatment, softening, RO, SEPTRON® EDI   316L SS execution

  Automatic hot water sanitization >80°C

  MULTIJOINT diaphragm bloc valve technology

  Easy modular upgrade option within the series

  0,5 - 10m³/h single skid or >10m³/h multi skid solutions

OSMOTRON®

OsmoVision

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PW/HPW Storage and DistributionStorage Tanks fed by BWT PW/HPW generation systems enable buffering of peak consumptions. Selection of the optimal tank size allows sizing of the PW/HPW generator for the most continuous efficient generation mode.

In storage and distribution systems the objective is to maintain the chemical and microbiological quality of the PW/HPW at constant high level to ensure that user points are supplied with the quality exceeding the requirements defined per USP/EP and providing suf-ficient safety margin to set alarm and action levels.

LOOPO C – standardized compact distribution, control, monitoring and sanitization for ambient temperature PW/HPW storage and distribution systems

  Open-skid system including STERITRON electrolytic ozone generators and BEWADES ozone destruct UV technology

  Calibrated online analytical instrumentation for flow, pressure, temperature, conductivity and ozone

  Optional calibrated TOC analyzer

  316L SS execution

  Continuous sanitization of the storage tank by electrolytic produced ozone

  Automatic and easy periodic sanitization with ozone of the complete storage/distribution system up the user points

  Optimal energy efficiency   NO insulation requirement for tank and loop piping

LOOPO C

Systems, Solutions, Services10

WFI / Pure Steam GenerationWater for injection (WFI) is the most critical raw material for paren-teral pharmaceutical production. As such the qualities at the point of use are regulated in the different international pharmacopeia´s such as USP, EP, JP. The EP is permitting distillation as the only method to produce WFI. Although some pharmacopeia´s allow alternative production technologies, distillation is the technology of choice and industry standard for the generation of WFI.

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For Pure Steam the USP has set the quality requirement for conden-sate of the pure steam identical to WFI quality.

1 MULTITRON – high efficiency multi effect distillation   316L SS construction

  Up to eight columns increasing the efficiency   Preheaters included

  Integrated cooler / condenser

  Optional variable WFI capacity control

2 VAPOTRON – fast reaction pure steam generator   316L SS construction

  Constant pure steam pressure at maximum demand

  Optional preheater

  Optional Degasifier   EN 285 compliant

MULTITRON multi effect distillation systems and VAPOTRON pure steam generators are available as individual units or as the unique COMBITRON system producing water for injection and pure steam in parallel.

WFI Storage and Distribution

3 LOOPO H – standardized compact distribution, control, monitor-ing and sanitization for hot WFI storage and distribution systems

  Open skid system including DTS (Double Tube Sheet) heat exchanger

  Calibrated online analytical instrumentation for flow, pressure, temperature, conductivity

  Optional calibrated TOC analyzer

  316L SS execution

  Optional automatic periodic sanitization with superheated water 121°C of the complete storage/distribution system up the user points

  Optional POU (point of use) DTS coolers and POU operator interface panels

Systems, Solutions, Services12

Validation, Qualification & Documentation – Successful Inspection GuaranteedBWT Pharma & Biotech systems are qualified in accordance with the requirements of FDA, cGMP, cGAMP, cUSP and cPh. Eur. The design and the documentation are based on the ´ISPE Engineer-ing Guide – Water and Steam Systems´ and ´Commissioning and Qualification of Pharmaceutical Water and Steam Systems´. The systems are designed and built in accordance with the actual regu-lations of PED, EMC, LV and the Machinery Directives and carry the CE symbol.

During each project, a validation engineer accompanies all project activities in order to ensure optimal coordination of all steps, from the URS (User Requirement Specification) through all stages of the V model to the FAT/SAT. All IQ/OQ checks and tests are as far as possible and practical executed in our workshop before the factory acceptance test. BWT systems leave the factory only after success-ful FAT, which verifies the execution, functionality and quality of the system. This procedure permits simple and fast installation and commissioning of the system on the customer‘s premises and limits the implementation risk at site.

Providing a compliant and uniform technical & qualification docu-mentation BWT will ensure clients compliance and comfort during inspections and audits. Transparent and well-structured information permits easy operation and maintenance of the systems. High qual-ity drawings with standard tag numbering provide the basis for quick assistance and support by our experienced service engineers.

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Automation The automation and control system is the brain and heart of every clean utility system. Executing the projects according to cGAMP requirements is the basis for best performance and results.

AQU@VIEW automation products are available for all systems and provide high quality process con-trol with validated open source software and interface graphics. All based on international well recognized premium control products such as Siemens or Rockwell.

Based on the approved P&ID, control concept and electrical wiring diagrams a detailed functional logic (FL) document is developed. Describing well-structured all functions, controls, sequencers, set-points, alarms, priorities etc. the FL is essential basis for the quali-fied programming and OQ testing. Transparent documented PLC program descriptions will provide a logical and easy to understand program structure that is free of any dead code.

Independent PLC-CPU´s for each skid unit provide maximum independ-ence and safety as well as enabling all loop checks, alarm checks, operational parameter etc. during the functional FAT. This ensures a perfect tested system before shipment to site.

BWT AQU@VIEW offers many value added optional features to enhance system control and comfort.

Comfortable visual interface graphics and innovative applications such as AQU@VIEW Data Logger in combination with AQU@VIEW Audit Trail allow GMP compliant monitoring of the entire system.

Embedded in your factory DCS system you can interface via AQU@VIEW Data Export Ethernet connection with each of the indi-vidual systems and extract and monitor all available data.

AQU@VIEW Remote Operation allows complete replication of the system HMI to your office computer or remote tablet and grant-ing you comfortable access and information of the system status. Wherever you are.

AQU@VIEW Remote Assistance enables skilled BWT engineers to support your operators via a safe VPN (Virtual Private Network) Internet connection in case of emergency.

With AQU@VIEW POU Management you can control and optimize all automatic user points in your clean media distribution system to ensure optimal supply and prioritizing.

Systems, Solutions, Services14

Customer ServicesConsistent performance in quality and quantity of the clean util-ity systems as well as maximum availability are critical to any pharmaceutical or related production process. To safely ensure the performance during the entire system life cycle regular and well documented maintenance as well as calibration of quality relevant process instrumentation is necessary.

AQU@SERVICE – customer service products

With maximum flexibility, ranging from AQU@SERVICE GMP scheduled preventive maintenance to AQU@SERVICE Complete full service packages including all wear and spare parts, allows you to configure your individual service demand.

Experienced and well trained field service engineers will provide cGMP conform service, maintenance of the complete installation and, with AQU@SERVICE Calibration, the routine calibration of all quality relevant instrumentation. An excellent documentation of all service activities and calibrations is self-evident.

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With AQU@SERVICE Documentation BWT keeps your system documentation up to date with all reports, calibration certifi cates, change controls, data sheets and manuals of updated parts and many more, for perfect inspections and audits.

Expert know-how combined with modern tools will support and service your installation around the globe – wherever you are. Our international team is available for you 365 days per year on a 24/7 basis and, with our AQU@SERVICE Hotline, assisting you in all questions regarding your clean media systems.

Together with local critical spares AQU@SERVICE Parts provides you with a central warehouse to supply validated high quality wear and spare parts for optimal system availability.

With BWT Pharma & Biotech AQU@SERVICE you can rely on one partner and one single point of contact for your clean media instal-lation – whereever you are!

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Manufacturing+ FAT

1.

Project Identifi cation

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Project Management

2.

Project Developement + Basic Engineering

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7.

Installation

3.

Project / ProposalPresentation

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Commissioning, Validation and

Training

4.

Planning + Detailed Engineering

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Customer Service and Operation

BWT Pharma & Biotech

Customer

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16 BWT – The Company

BW

T 14

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Find us on www.bwt-pharma.com

www.bwt-pharma.com

Best Water Technology Group (BWT) is Europe’s leading water technology compa-ny. Our water partner network comprises the group’s 3,300 employees and thou-sands of plumbers, planners, architects and hygiene experts. Our Research & Develop-ment teams, using state-of-the-art methods, work on new processes and materials to create products that are both ecological and economical. Looking ahead, a key de-velopment issue is a reduction in the prod-ucts’ use of operating resources and energy consumption and the resulting minimisation of CO

2 emissions.

Whether at the place where the water pipe enters the building (‘point of entry’) or at the tapping point (‘point of use’), BWT’s trend-setting ‘Made in Europe’ products have proved their quality millions of times over in the treatment of: drinking water, mineral water and ultrapure wa-ter for the pharmaceuti-cal industry; water for swimming pools; heat-ing and process wa-ter; boiler and cooling water; and water for air-condition-ing. BWT’s wide-rang-ing innovations guarantee maximum safety, hygiene and health in the daily use

of water – that precious elixir of life. These innovations, among others, include: SEP-TRON®, the world’s fi rst electrodeionisation module (EDI) with spiral wrap; manganese oxide activation (MDA) – a method for effec-tive manganese removal; AQA total bipolar technology for chemical-free limescale pro-tection; SANISAL – the world’s fi rst regenera-tion salt for softening water systems, which also works as a disinfectant; and the new, revolutionary Mg2+ technology that improves the taste of fi ltered water, coffee and tea. Through its unique, high effi ciency mem-branes for fuel cells and batteries, BWT is creating a cleaner, more sustainable energy supply for the 21st century.

BWT – For You and Planet Blue signifi es that our mission is to take ecological,

economical and social re-sponsibility, to provide

our customers and partners with the best products, sys-

tems, technologies and services in all areas of water treat-ment and, at the same time, to make a valuable contri-bution to preserv-

ing the global resources of our blue

planet.